Acquired Cystic Disease of the Kidney and Renal Cell Carcinoma - part 3 doc

I observed no difference in parenchymal atrophy or cyst regression of the native kidney after renal transplantation, or in the development of new cysts, whether or not cyclosporin was us

which will resolve the uremic environment (2) The blood fl ow in the native kidney decreases with a decrease in osmotic pressure load This is caused by a decrease in the urine volume from the native kidney after transplantation of a graft kidney (3) The cysts are smaller and have more communication with renal tubules and glomeruli

in ACDK than in ADPKD [30] (4) If there are cyst proliferation factors [46], they may not be removed by dialysis, but they may be excreted into the urine by the graft kidney even if its renal function is not adequate (5) Immunosuppressants induce shrinkage

of renal cysts However, there are no data that support this mechanism, and there is

a report that cysts are more likely to develop after renal transplantation if cyclosporin (CsA) is used [47] Therefore, using my own protocol, I examined the patients with highly functional grafted kidneys from a group who had received renal transplanta-tion using cyclosporin I observed no difference in parenchymal atrophy or cyst regression of the native kidney after renal transplantation, or in the development of new cysts, whether or not cyclosporin was used [48] (6) Cells of the cyst wall in ACDK decrease due to apoptosis, causing a decrease in cysts Eventually, ACDK may trans-form into the original atrophic kidneys

Recently, a 20% decrease in the kidney volume was also observed in a patient in whom renal function had just begun to improve, and the graft kidney had excreted only 400 ml/day urine (Fig 26) I now present some cases of patients in which the cysts disappeared almost completely as early as 2 weeks after transplantation The

fi rst patient (Fig 27) was a 52-year-old man who had received dialysis for 231 months Fig 25 Changes in kidney volume after renal transplantation A decrease in kidney volume due to the regression of acquired cysts was observed immediately after transplantation

Fig 26 The rate of decrease in kidney volume during the fi rst month after renal transplanta-tion The kidney volume began to decrease because of a regression of cysts even when the urine volume was low due to acute tubular necrosis Case 1 showed an early decrease, and Case 2 showed a slow decrease

Fig 27 Regression of acquired renal cysts early after renal transplantation Regression began even during the period of acute tubular necrosis in a case that showed early regression (Case 1

in Fig 26)

(19 years and 3 months) In November 1997, hemodialysis was initiated for terminal renal failure due to chronic glomerulonephritis In February 1997, the patient received

a renal transplantation from a cadaveric donor at our hospital, and underwent the

fi rst postoperative CT on day 14 after surgery In this patient, renal cysts were observed

on preoperative CT, and the bilateral kidney volume had increased to 417 ml Urine began to be excreted on day 4 after surgery, the urine volume exceeded 1000 ml on day 12, and the patient was weaned from dialysis on day 14 On this day, the fi rst CT after transplantation showed that the bilateral kidney volume was reduced to 249 ml,

or 60% of the preoperative value During this period, the patient’s serum creatinine level decreased from about 9 mg/dl immediately after the operation to about 3 mg/dl (Fig 27) In the second case, the patient’s bilateral kidney volume decreased to 75%

of the preoperative value (100%) after 1 month, to 17% after 1 year, and to 13% (or

44 ml) after 3 years In this patient, the preoperative size of the cysts was smaller than

in the fi rst patient, and they occurred in groups (Fig 28) The regression of cysts after renal transplantation may provide an important clue to an evaluation of the etiology

of ACDK

Thereafter, detailed examinations of cysts in native kidneys after renal transplanta-tion showed that the cysts remained regressed if the renal functransplanta-tion was adequate, but that new cysts developed occasionally [49] These cysts may have been simple renal cysts However, an exploration for tumors is essential if cysts in the native kidney do not regress [50] or if they enlarge [51] after renal transplantation [52,53]

Fig 28 Regression of acquired renal cysts early after renal transplantation A case that showed slow regression (Case 2 in Fig 26)

Fig 29 Many cysts appeared in the native

kidney (above) with the decline in the

func-tion of the graft kidney Since the period of

chronic renal failure was short (below), fewer

cysts developed in the graft kidney than in the

native kidney (Reproduced from [54], with

permission from Elsevier Inc.)

Table 2 Clinical characteristics of acquired cysts in acquired cystic disease of the kidney

1 High incidence of renal cell carcinoma

2 Relationship to the duration of chronic renal failure and hemodialysis

3 Male preponderance

4 No relationship to dialysis modality

5 No relationship to dialysis membrane

6 Regression of acquired cysts after renal transplantation

Naturally, if the function of the graft kidney is reduced, cysts again increase in the native kidney A small number of cysts also appear in the graft kidney if reduced function persists [54] (Fig 29)

The clinical characteristics of acquired cysts in ACDK are summarized in Table 2

9 Diagnosis of Acquired Cystic Disease of the Kidney

Acquired cystic disease of the kidney can be diagnosed if a total of three to fi ve cysts are found in one kidney (or three to fi ve cysts in both kidneys combined according

to some authors) on an imaging study [11] The imaging technique may be either

ultrasonography or a CT scan In ACDK, the cysts are characteristically small, with a diameter of 0.02–2 cm, and occur in large numbers In cross sections, a large number

of small cysts are observed, but sometimes only one cyst on the top can be seen by

CT or ultrasonography (see Fig 11) Cysts 0.5 cm or greater in diameter can usually

be detected by imaging techniques, while smaller cysts are undetectable However, imaging techniques are useful not only for the diagnosis of renal cell carcinoma, which is rarely symptomatic, but also for an evaluation of the severity of cystic changes, and the risks of complications such as renal cell carcinoma and retroperi-toneal bleeding

10 Causes of Acquired Cystic Disease of the Kidney

Why do cysts develop and grow in the kidneys in end-stage renal failure or after the initiation of dialysis? At present, the causes or pathogenic mechanism of such cysts remain unclear During the past 26 years, many hypotheses have been proposed, as shown in Table 3, including proliferation of the tubular epithelium due to uremic metabolites and growth factors, ischemia, factors related to hemo dialysis such as plasticizers, obstruction of the renal tubules by oxalate crystals, b2-microglobulins, etc., hormone imbalance, trace elements such as vanadium, and regional acidosis [10] However, all these hypotheses, with the exception of proliferation of the tubular epithelium due to uremic metabolites and growth factors, are currently considered

to be unlikely

Since cysts enlarge during long-term dialysis whether it is hemodialysis or CAPD, and since they regress after successful renal transplantation [44], I speculated that proliferation of the tubular epithelium due to uremic metabolites and growth factors

is involved in the mechanism of cyst formation (Table 3), and that these uremic metabolites and growth factors are mainly active in males However, these factors remain to be identifi ed

It is also of interest that the cyst fl uid of ACDK showed a different pattern compared with the cyst fl uid of ADPKD or of simple renal cysts on examination using a surface-enhanced laser desorption/ionization time-of-fl ight mass spectrometer (SELDI-TOF-MS) and ProteinChips These fi ndings are being analyzed (Fig 30)

Table 3 Hypotheses of the pathogenic mechanisms of acquired cystic disease of the kidney

1 Epithelial hyperplasia theory due to:

Uremic metabolites and/or growth factors due to the loss of functioning nephrons

Ischemia

A dialysis-related substance (plasticizer, etc)

2 Tubular obstruction theory due to:

Oxalate crystals, β 2 -microglobulin, etc

3 Other theory (trace element-vanadium, regional acidosis)

11 Twenty-Year Follow-up of Acquired Cystic Disease of the Kidney

We followed up 96 patients who had undergone renal function replacement therapy for chronic glomerulonephritis since 1979 [13] During this period, 44 died, 36 required hemodialysis (19 males and 17 females) and could be followed up for 20 years, and 7 were managed for 20 years by renal transplantation alone During this period, renal cell carcinoma occurred in 6 patients and 4 of these died, but the deaths were not due to the renal cell carcinoma Table 4 shows the causes of death in the 44 patients Enlargement of the kidneys was observed more frequently in male patients than in female patients Figure 31 shows the severity of cystic changes After 20 years, advanced grade 4 cystic changes were observed in many male patients When the male patients were divided into those aged less than 40 years and those aged 40 years and above, and the percentages of those who showed a 4-fold or greater enlargement of the kidneys were compared, the kidneys were enlarged due to cysts more often in those aged less than 40 years In other words, cysts among male patients were found

to be more likely to develop in relatively young subjects

Figure 32 shows the CT scans for this study Images of a 47-year-old man who had undergone hemodialysis for 1 year and 7 months are shown on the left His kidney

Fig 30 A heat-map showing the results of proteome analysis of cyst fl uid by SELDI-TOF-MS Proteins in the cyst fl uid of acquired renal cysts are classifi ed into different clusters The clusters indicate, from left to right, acquired cystic disease of the kidney without renal cell carcinoma, acquired cystic disease of the kidney with renal cell carcinoma, and autosomal dominant poly-cystic kidney disease Proteins in some cysts of acquired poly-cystic disease of the kidney with renal cell carcinoma revealed clusters which were similar to those of autosomal dominant polycystic kidney disease

Fig 31 A 20-year follow-up of acquired cystic disease of the kidney The graphs show the fre-quencies of the grades of cysts during the follow-up Severe grade-4 cystic changes were observed

in many of the male patients after 20 years (Reproduced from [13], with permission from Dustri-Verlag Dr Karl Feistle)

Table 4 Causes of death in patients who died during a 20-year

follow-up of acquired cystic disease of the kidney (Reproduced

from [13], with permission from Dustri-Verlag Dr Karl Feistle)

Causes of death in 44 patients Myocardial infarction 8 ( + RCC) (18.2%)

Cerebrovascular accident 7 ( + RCC) (15.9%)

RCC, renal cell carcinoma

volume, which was originally 62 ml, decreased slightly to 54 ml after 1 year, but increased markedly to 467 ml after 15 years, and to 665 ml after 20 years, but with increases in the number of cysts Images of a 28-year-old woman who had undergone dialysis for 2 years and 8 months are shown on the right Very few cysts developed during the 20-year follow-up period, and her kidney volume, which was originally

65 ml, was 56 ml, 112 ml, and 134 ml after 1 year, 15 years, and 20 years, respectively, which were much smaller increases To summarize the results of our 20-year

follow-up, cystic changes in the kidney were more notable in male patients, and the kidney volume showed marked increases, particularly in young male patients Although renal cell carcinoma was detected in six patients during this period, they all died of unrelated reasons

Fig 32 A 20-year follow-up of acquired cystic disease of the kidney Images of a male and a female patient during the follow-up Sex differences are evident (Reproduced from [13], with permission from Dustri-Verlag Dr Karl Feistle)

Chapter 3

Renal Cell Carcinomas in

Dialysis Patients

1 The Two Types of Renal Cell Carcinoma in

Dialysis Patients

Two types of renal cell carcinoma (RCC) are found in dialysis patients, i.e., those that complicate and those that do not complicate acquired cystic disease of the kidney (ACDK) The type that complicates ACDK accounts for 81% of all renal cell carcinomas, and is observed more frequently in male patients, younger patients, and patients who have been managed longer by dialysis than the type which does not complicate this disease [55] Histologically, the type of renal cell carcinoma that complicates ACDK is most often papillary renal cell carcinoma, which is closely related to cysts On the other hand, the type of renal cell carcinoma that does not complicate ACDK is frequently observed in elderly patients, its occurrence is unre-lated to the duration of dialysis therapy, and the percentage of clear cell carcinomas

is high

2 Histology

When acquired cystic disease of the kidney (ACDK) is complicated by renal cell car-cinoma, the kidney size varies with the duration of dialysis and the sex of the patient, and may become indistinguishable from that of kidneys with autosomal dominant polycystic kidney disease (ADPKD) [23]

Figure 33 shows a kidney of a 64-year-old man who had received hemodialysis for

13 years Multiple cysts were observed in the bilateral kidneys, and a mass 4.5 cm in diameter was noted in the lower pole of the right kidney When the resected kidney was cut along the same planes as the CT slices (Fig 34), renal cell carcinomas (repre-sented as areas with red diagonal lines), cysts with monolayer epithelium (surrounded

by a black line), multilayered so-called atypical cysts (surrounded by a red or blue line), and solid adenomas (represented as areas of solid color) were distributed in a multicentric pattern Such simultaneous presence of cysts, atypical cysts, solid adeno-mas, and renal cell carcinomas in the same kidney, their multicentric occurrence, and the presence of precancerous lesions are histological characteristics of ACDK [1,11] Renal cell carcinoma is bilateral in 9%–15% of patients [56–58]

Fig 33 A macroscopic image of acquired cystic disease of the kidney in a 64-year-old man with a 13-year history of hemodialysis A renal cell carcinoma can be seen in the lower pole

Fig 34 Cross-sectional pathology of the resected kidney shown in Fig 33 Cysts, atypical cysts, solid adenoma, and renal cell carcinoma were seen in the same kidney

As shown in Fig 35, microscopic examination showed that this patient had (a) proximal tubules with epithelial hyperplasia, (b) cysts with monolayer epithelium, (c) atypical cysts with multilayered epithelium, (d) adenoma, and (e) papillary renal cell carcinoma

Acquired cystic disease of the kidney characteristically shows precancerous lesions such as atypical cysts and adenomas The presence of the brush border (microvilli)

in the cyst epithelium and the composition of the cyst fl uid suggest a proximal tubular origin for the cysts (both cysts with monolayer epithelium and atypical cysts) On examination of their proliferative ability using vimentin, EGF receptor, and c-erb B2,

73% of atypical cysts were positive for vimentin, 95% were positive for EGF receptor [59], and 100% were positive for c-erb B2 [59,60] However, only 9.7% of the samples

Fig 35. Microscopic images a Hyperplastic proximal tubules b Cyst with monolayer epi-thelium c Atypical cyst with multilayer epiepi-thelium d Adenoma e Papillary renal cell

carcinoma